Restless Legs Syndrome
Victims seriously afflicted with Restless Leg Syndrome (RLS; also known as Ekbom's syndrome), are virtually unable to remain seated or even to stand still. Activities that require maintaining motor rest and limited cognitive stimulation, such as transportation (car, plane, train, etc.) or attending longer meetings, lectures, movies or other performances, become difficult if not impossible. Tortured by these sensations which become more severe at night, RLS patients find sleep to be virtually impossible, adding to the diminishing quality of their lives. The urge to move, which increases over periods of rest, can be completely dissipated by movement, such as walking. However, once movement ceases, symptoms return with increased intensity. If an RLS patient is forced to lie still, symptoms will continue to build like a loaded spring and, eventually, the legs will involuntary move, relieving symptoms immediately. Rhythmic or semi-rhythmic movements of the legs are observed if the patient attempts to remain laying down (Pollmacher and Schulz 1993). These movements are referred to as dyskinesias-while-awake (DWA) (Hening et al. 1986) or more commonly, periodic limb movements while awake (PLMW).
Clinically, RLS is indicated when four diagnostic criteria are met: (1) a sensation of an urge to move the limbs (usually the legs); (2) motor restlessness to reduce sensations; (3) when at rest, symptoms return or worsen; and (4) marked circadian variation in occurrence or severity of RLS symptoms; that is, symptoms worsen in the evening and at night (Allen and Earley 2001a). First recognized by Willis in 1685, RLS has been misunderstood and confused with periodic limb movements in sleep (PLMS; which may be a part of RLS, but does not define RLS), periodic limb movement disorder (PLMD; a sleep disorder) and nocturnal (or sleep) myoclonus (Allen and Earley 2001a).
Iron and Dopamine Concentrations are Intertwined Factors in RLS
Lack of iron and reduced dopamine synthesis in the brain are important factors in RLS (Ekbom 1960, Nordlander 1953). Dopamine is a neural transmitter synthesized in the brain that is essential for proper central nervous system (CNS) function. In the synthesis of dopamine, iron is a cofactor for the enzyme tyrosine hydroxylase, which is the rate-limiting step in dopamine metabolism (Cooper et al. 1991). Iron in the dopaminergic system appears to be an important component in RLS pathophysiology (Chesson A L et al. 1999, Ekbom 1960, Hening et al. 1999, Montplaisir et al. 1991).
Because iron is a co-factor for tyrosine hydroxylase in dopamine synthesis, dopamine is reduced. When chelators (substances that bind metals such as iron, and make them physiologically unavailable) are administered to rats having excessive brain iron, they were effective in reducing dopamine and dopamine turnover (Ward et al. 1995). Studies in iron-deficient animals have also demonstrated decreases in dopamine receptors (Ben-Shachar et al. 1985, Ward et al. 1995), dopamine transporter function and receptor density with an elevation in extracellular dopamine (Erikson et al. 2000, Nelson et al. 1997). These observations in rats are also observed in RLS patients. For example, a decrease in dopamine receptors has been observed in basal ganglia (Staedt et al. 1995, Turjanski et al. 1999). RLS patients have 65% less cerebral spinal fluid (CFS) ferritin (an important iron storage protein) and three-fold more CSF transferrin (iron transport protein in blood and body fluids), despite normal serum levels of ferritin and transferrin in both RLS and controls (Earley et al. 2000). Iron concentrations vary throughout the brain; RLS patients have less iron in the substantia nigra and in the putamen parts of the brain, both sites of dopamine synthesis (Allen et al 2001). In general, decreased ferritin levels are indicative of RLS severity (O'Keeffe et al. 1994, Sun et al. 1998). These observations indicate that the ability of the brain to transport or store iron is abnormal in idiopathic RLS (RLS having no apparent cause)
TABLE 1Side effects of current treatments for Restless Legs Syndrome (RLS)1MedicationDisease2Side effects% affected3levodopa/carbidopaParkinsondyskinesia (inability to control movements), nausea, hallucinations4-17Pergolide w/Parkinsondyskinesia, nausea, hallucinations, rhinitis (mucous membrane7-62levodopa/carbidopainflammation), constipation, painPramipexoleParkinsonsomnolence, insomnia, nausea, constipation, hallucinations9-28Narcotic analgesicsPain controlrespiratory depression, nausea, somnolence, pruritus (severe itching),none reportedconstipation, urinary retentionClonazepamEpilepsysomnolence, depression, in-coordination6-37TriazolamInsomniadrowsiness, dizziness, memory impairment1-14GabapentinEpilepsyfatigue, dizziness, somnolence, ataxia (unable to coordinate muscular11-19 movement)CarbamazepineEpilepsyfetal malformation, rash, hyponatremia (blood sodium deficiency),1-33hepatotoxicity, blood disorders, ataxia, gastro-intestinal problems, sexualdysfunction, toxicityClonidineHypertensionreduced blood pressure, dermatitis, systemic side effects (dry mouth,8-89somnolence, dizziness, headache)intravenous iron dextraniron deficienciesanaphylaxis, possibility resulting in death0.3-1.7 (Fishbane(Fishbane et al.et al. 1996,1996) andHamstra et al.random sampling1980)(Hamstra et al.1980)1Table derived from (Chesson AL et al. 1999), except for intravenous iron dextran. 2Studies were performed on patients suffering from the indicated disease, not RLS, with the indicated drug. 3As reported in the studies referenced within (Chesson AL et al. 1999). See Chesson et al. 1999 for more information. The percent (&) range is derived from the reported percentages for each side effect; thus in the first example, 12-17% suffered from dyskinesia, 6% from nausea and 4% from hallucinations; the reported range is 4-17%. 
Treating RLS
Current treatments for RLS are varied and plagued with undesirable side effects (see Table 1). Therapies have included the administration of dopamine agonists (substances that promote the production of dopamine), other dopaminergic agents, benzodiazepines, opiates and anti-convulsants. In cases where RLS results from a secondary condition, such as pregnancy, end-stage renal disease, erythropoietin (EPO) treatment and iron deficiency, removing the condition, such as giving birth or treating with traditional iron supplementation, can reduce or eliminate symptoms in at least some cases (Allen and Earley 2001a). However, RLS resulting from non-secondary conditions “idiopathic” RLS), presents a greater treatment challenge.
Dopaminergic agents such as levodopa generally provide effective initial treatment, but with continued use, tolerance and symptom augmentation occur in about 80% of RLS patients (Allen and Earley 1996); this complication is also common for dopamine agonists (Earley and Allen 1996, Silber et al 1997). The other alternatives, benzodiazepines, opiates and anti-convulsants are not as uniformly effective as the dopamine agents (Chesson AL et al. 1999, Hening et al. 1999). Despite changes in ther treatment regimes, 15-20% of patients find that all medications are inadequate because of adverse effects and limited treatment benefit (Earley and Allen 1996).
Because of the link between iron and dopamine synthesis, iron administration would appear to be a simple and safe treatment to increase body iron stores. An obvious choice is oral administration of iron since such administration is simple and inexpensive. In fact, RLS patients with iron deficiency respond dramatically to oral iron supplements (Ekbom 1960, O'Keeffe et al. 1994). However, in RLS patients with normal serum ferritin levels, the benefits of oral iron therapy decrease inversely to baseline serum ferritin levels: the higher the ferritin at the time of initiating therapy, the less pronounced the benefits (O'Keeffe et al. 1994). This approach to raise body stores of iron is ineffective because the intestinal epithelium controls iron absorption, responding not to dopamine synthesis cues, but to serum iron levels (Conrad et al. 1999). Therefore, oral doses of iron are ineffective, and not tolerated. To increase body stores of iron when serum ferritin levels are normal, methods that bypass intestinal epithelial regulation would need to be used. For example, in the anemia of chronic disease, iron absorption and transport is dramatically impaired and serium ferritin levels being elevated does not accurately reflect stored iron levels in the body. Also in the anemia of chronic disease the only effective way to deliver adequate iron for erythropoiesis to a deprived system is by intervenus administration.
Intravenous administration of iron circumvents the problems and ineffectiveness of orally-administered iron for those RLS patients with normal serum ferritin levels. In fact, intravenous administration of iron dextran solutions, such as INFeD® (Watson Pharma, Inc.; Corona, Calif. (having an average apparent molecular weight of 165,000 g/mole with a range of approximately±10%), and Dexferrum® (American Regent Inc., Shirley, N.Y.) (referred to collectively as “IDI”) successfully treats RLS. However, the dosage is high—1000 mg/administration; or about two- to ten-fold more than the usual dose when used to treat other conditions. While IDI offers hope to some RLS patients, it also suffers from significant disadvantages: not only is the dosage high, but also dextran causes anaphylaxis in about 1.7% of the population (Fishbane et al. 1996), a life threatening condition; just less than 50% or those suffering anaphylaxis die.